One gene, many proteins – new insights into rare disease mechanisms

Individual genes have been shown to produce multiple proteins, providing a potential insight into rare diseases that have previously lacked a clear explanation.

Researchers have found that single genes can result in the production of multiple proteins, rather than just a single 'known' product. Mutations in these genes can potentially affect multiple proteins and can result in atypical presentations of diseases in terms of symptoms and severity.

'We hope this work demonstrates the importance of considering whether a gene of interest makes multiple versions of a protein, and what the role of each version is in health and disease,' said Jimmy Ly, PhD student at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and first author of the paper, published in Molecular Cell.

When proteins are translated from genetic code, there are typically 'start' and 'stop' sequences, or codons, to mark where translation should begin and end. However, as some genetic sequences may naturally contain multiple start codons, proteins may be produced that are longer or shorter than intended. These proteins also contain identifying sequences, similar to postcodes, that communicate where in the cell they need to be sent, allowing researchers to track them down. Depending on its destination within the cell, each protein can have a different impact.

In collaboration with Dr Mark Fleming from Boston Children's Hospital, Massachusetts, the researchers analysed anonymised data from patients with a rare congenital form of anaemia caused by mutations in the TRNT1 gene called sideroblastic anaemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Ly identified TRNT1 as a gene that produces two forms of its protein, one of which ends up in the mitochondria, while the other is transported to the nucleus.

While most patients in the study had mutations that eliminated both proteins, the researchers identified one patient missing only the mitochondrial variant, and another who was missing solely the nuclear variant. After comparing their findings, Dr Fleming was able to identify that these patients displayed atypical presentations of SIFD. Both patients presented as developmentally normal, although the patient missing only the nuclear protein was anaemic. The patient who was missing the mitochondrial protein did not have chronic anaemia, but did display other immune symptoms, including a lifelong history of fever.

'As my lab transitions to this new focus, I've heard many stories from people trying to navigate a rare disease and just get answers, and that has been really motivating to us, as we work to provide new insights into the disease biology,' stated lead author Professor Iain Cheeseman from the Whitehead Institute.

A rare disease is defined as affecting fewer than one in 2000 people and the team's long-term ambition is to provide a better understanding of the wider mechanics behind such diseases. According to Ly, there is also potential for personalised treatments according to the specific genetic mutations behind an individual's presentation of a disease.

Recently, the UK government announced its commitment to accelerate the development of treatments for rare diseases (see BioNews 1314).